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Background: Tumors are the second most common cause of death in humans worldwide, second only to cardiovascular and cerebrovascular diseases. Although methods and techniques for the treatment of tumors continue to improve, the effect is not satisfactory. These may lack effective therapeutic targets. This study aimed to evaluate the value of SNHG12 as a biomarker in the prognosis and clinical characteristics of various cancer patients., Methods: We analyzed SNHG12 expression and plotted the survival curves of all cancer samples in the TCGA database using the GEPIA tool. Then, we searched for eligible papers up to April 1, 2019, in databases. Next, the data were extracted from studies examining SNHG12 expression, overall survival and clinicopathological features in patients with malignant tumors. We used Review Manager 5.3 and Stata 15 software to analyze the statistical data., Results: In the TCGA database, abnormally high expression of SNHG12 in tumor samples indicates that the patient has a poor prognosis. Results of meta-analysis is that SNHG12 high expression is related to low overall survival (HR = 2.72, 95% CI = 1.95-3.8, P < 0.00001), high tumor stage (OR = 3.94, 95% CI = 2.80-5.53, P < 0.00001), high grade (OR = 2.04, 95% CI = 1.18-3.51, P = 0.01), distant metastasis (OR = 2.20, 95% CI = 1.40-3.46, P = 0.0006), tumor size (OR = 2.79, 95% CI = 1.89-4.14, P < 0.00001), and lymph node metastasis (OR = 2.66, 95% CI = 1.65-4.29, P < 0.0001)., Conclusions: Our study confirmed that the high expression level of SNHG12 is closely related to the clinicopathological characteristics and prognosis of patients and is a new predictive biomarker for various cancer patients., (© 2021. The Author(s).)

Intracranial aneurysm (IA) is an abnormal focal dilation of an artery in the brain that results from a weakening of the inner muscular layer of a blood vessel wall. IAs represent the most common etiology of nontraumatic subarachnoid hemorrhage (SAH). Despite technological advances in the treatment and use of new diagnostic methods for IAs, they continue to pose a significant risk of mortality and disability. Thus, early recognition of IA with a high risk of rupture is crucial for the stratification of patients with such a formidable disease. MicroRNAs (miRNA) are endogenous noncoding RNAs of 18-22 nucleotides that regulate gene expression at the post-transcriptional level through interaction with 3'-untranslated regions (3'UTRs) of the target mRNAs. MiRNAs are involved in the pathogenesis of IAs, including in the mechanisms of formation, growth, and rupture. It is known that in many biological fluids of the human body, such as blood or cerebrospinal fluid (CSF), numerous miRNAs, called circulating miRNAs, have been detected. The expression profile of circulating miRNAs represents a certain part of the cells in which they are modified and secreted in accordance with the physiological or pathological conditions of these cells. Circulating miRNAs can be secreted from cells into human biological fluids in extracellular vesicles or can be bound to Ago2 protein, which makes them resistant to the effects of RNAse. Therefore, circulating miRNAs are considered as new potential biomarkers of interest in many diseases, including IA., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Exosomal microRNAs (miRNAs) play an essential role in near and distant intercellular communication and are potential diagnostic and prognostic biomarkers for various cancers. This study focused on evaluation of exosomal miR-2276-5p in plasma as a diagnostic and prognostic biomarker for glioma., Methods: Plasma exosomes from 124 patients with glioma and 36 non-tumor controls were collected and subjected to quantitative real-time polymerase chain reaction (qRT-PCR) analysis for the exosomal miR-2276-5p expression. Bioinformatic analyses were performed to identify a gene target, and CGGA and TCGA databases were checked for evaluation of prognostic relevance., Results: The exosomal miR-2276-5p in glioma patients had a significantly decreased expression, compared with non-glioma patients ( p < 0.01). Receiver operating characteristics (ROC) curve analyses were observed to regulate the diagnostic sensitivity and specificity of miR-2276-5p in glioma; the area under the curve (AUC) for miR-2276-5p was 0.8107. The lower expression of exosomal miR-2276-5p in patients with glioma correlated with poorer survival rates. RAB13 was identified as the target of miR-2276-5p which was high in glioma patients, especially those with higher tumor grades and correlated with poor survival., Conclusion: The circulating exosomal miR-2276-5p is significantly reduced in the plasma of glioma patients, and thus, it could be a potential biomarker for patients with glioma for diagnostic and/or prognostic purposes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sun, Sun, Gareev, Yan, Chen, Ahmad, Zhang, Zhao, Beylerli, Yang and Zhao.)

The tumor microenvironment plays an important role in tumor progression. Hyaluronic acid (HA), an important component of the extracellular matrix in the tumor microenvironment, abnormally accumulates in a variety of tumors. However, the role of abnormal HA accumulation in glioma remains unclear. The present study indicated that HA, hyaluronic acid synthase 3 (HAS3), and a receptor of HA named CD44 were expressed at high levels in human glioma tissues and negatively correlated with the prognosis of patients with glioma. Silencing HAS3 expression or blocking CD44 inhibited glioma cell proliferation in vitro and in vivo. The underlying mechanism was attributed to the inhibition of autophagy flux and maintaining glioma cell cycle arrest in G1 phase. More importantly, 4-methylumbelliferone (4-MU), a small competitive inhibitor of Uridine diphosphate (UDP) with the ability to penetrate the blood-brain barrier (BBB), also inhibited glioma cell proliferation in vitro and in vivo. Thus, approaches that interfere with HA metabolism by altering the expression of HAS3 and CD44 and the administration of 4-MU potentially represent effective strategies for glioma treatment.

Background: Long noncoding RNAs (lncRNAs) contribute to multiple biological processes in human glioblastoma (GBM). However, identifying a specific lncRNA target remains a challenge. In this study, bioinformatics methods and competing endogenous RNA (ceRNA) network regulatory rules were used to identify GBM-related lncRNAs and revealed that OXCT1 antisense RNA 1 (OXCT1-AS1) is a potential therapeutic target for the treatment of glioma., Methods: Based on the Gene Expression Omnibus (GEO) dataset, we identified differential lncRNAs, microRNAs and mRNAs and constructed an lncRNA-associated ceRNA network. The novel lncRNA OXCT1-AS1 was proposed to function as a ceRNA, and its potential target miRNAs were predicted through the database LncBase Predicted v.2. The expression patterns of OXCT1-AS1 in glioma and normal tissue samples were measured. The effect of OXCT1-AS1 on glioma cells was checked using the Cell Counting Kit 8 assay, cell colony formation assay, Transwell assay and flow cytometry in vitro. The dual-luciferase activity assay was performed to investigate the potential mechanism of the ceRNA network. Finally, orthotopic mouse models of glioma were created to evaluate the influence of OXCT1-AS1 on tumour growth in vivo., Results: In this study, it was found that the expression of lncRNA OXCT1-AS1 was upregulated in both The Cancer Genome Atlas (TCGA) GBM patients and GBM tissue samples, and high expression of OXCT1-AS1 predicted a poor prognosis. Suppressing OXCT1-AS1 expression significantly decreased GBM cell proliferation and inhibited cell migration and invasion. We further investigated the potential mechanism and found that OXCT1-AS1 may act as a ceRNA of miR-195 to enhance CDC25A expression and promote glioma cell progression. Finally, knocking down OXCT1-AS1 notably attenuated the severity of glioma in vivo., Conclusion: OXCT1-AS1 inhibits glioma progression by regulating the miR-195-5p/CDC25A axis and is a specific tumour marker and a novel potential therapeutic target for glioma treatment.

Background: Glioma is the most common malignant brain tumor in adults. The standard treatment scheme of glioma is surgical resection combined alternative radio- and chemotherapy. However, the outcome of glioma patients was unsatisfied. Here, we aimed to explore the molecular and biological function characteristics of GPX7 in glioma., Methods: The multidimensional data of glioma samples were downloaded from Chinese Glioma Genome Atlas (CGGA). RT-qPCR method was used to identify the expression status of GPX7. Kaplan-Meier curves and Cox regression analysis were used to explore the prognostic value of GPX7. Gene Set Enrichment Analysis (GSEA) was applied to investigate the GPX7-related functions in glioma., Results: The results indicated that the expression of GPX7 in glioma was higher compared to that in normal brain tissue. Univariate and multivariate Cox regression analyses confirmed that the expression value of GPX7 was an independent prognostic factor in glioma. The GSEA analysis showed that GPX7 was significantly enriched in the cell cycle pathway, ECM pathway, focal adhesion pathway, and toll-like receptor pathway., Conclusions: The GPX7 was recommended as an independent risk factor for patients diagnosed with glioma for the first time and GPX7 could be potentially used as the therapy target in future. Furthermore, we attempted to explore a potential biomarker for improving the diagnosis and prognosis of patients with glioma.

Glioblastoma multiforme (GBM) is the most aggressive primary tumor of the central nervous system. As biomedicine advances, the researcher has found the development of GBM is closely related to immunity. In this study, we evaluated the GBM tumor immunoreactivity and defined the Immune-High (IH) and Immune-Low (IL) immunophenotypes using transcriptome data from 144 tumors profiled by The Cancer Genome Atlas (TCGA) project based on the single-sample gene set enrichment analysis (ssGSEA) of five immune expression signatures (IFN-γ response, macrophages, lymphocyte infiltration, TGF-β response, and wound healing). Next, we identified six immunophenotype-related long non-coding RNA biomarkers (im-lncRNAs, USP30-AS1, HCP5, PSMB8-AS1, AL133264.2, LINC01684, and LINC01506) by employing a machine learning computational framework combining minimum redundancy maximum relevance algorithm (mRMR) and random forest model. Moreover, the expression level of identified im-lncRNAs was converted into an im-lncScore using the normalized principal component analysis. The im-lncScore showed a promising performance for distinguishing the GBM immunophenotypes with an area under the curve (AUC) of 0.928. Furthermore, the im-lncRNAs were also closely associated with the levels of tumor immune cell infiltration in GBM. In summary, the im-lncRNA signature had important clinical implications for tumor immunophenotyping and guiding immunotherapy in glioblastoma patients in future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gao, Wang, Han, Lu, Zhang, Zhang, Wang, Yang, Jiang, Wu, Chen and Zhao.)

MicroRNAs (miRNAs) are non-coding RNAs with a length of 18-22 nucleotides that regulate about a third of the human genome at the post-transcriptional level. MiRNAs are involved in almost all biological processes, including cell proliferation, apoptosis, and cell differentiation, but also play a key role in the pathogenesis of many diseases. Most miRNAs are expressed within the cells themselves. Due to various forms of transport from cells like exosomes, circulating miRNAs are stable and can be found in human body fluids, such as blood, saliva, cerebrospinal fluid, and urine. Circulating miRNAs are of great interest as potential noninvasive biomarkers for tumors, lipid disorders, diabetes mellitus, and cardiovascular diseases. However, the possibility of their use in the clinic is limited, and this is associated with a number of problems since currently there are significant differences between the procedures for processing samples, methods of analysis, and especially strategies for standardizing results. Moreover, miRNAs can represent not only potential biomarkers but also become new therapeutic agents and be used in modern clinical practice, which again confirms the need for their study.

Our study aimed to determine the effect of the neutrophil-lymphocyte ratio on the prognosis of adult patients with acute stroke. We searched the Web of Science, PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure databases and selected all of the potentially eligible studies. From the included studies, we extracted characteristics such as the stroke type and acquisition time until routine blood collection and the odds ratios across studies. The 95% confidence intervals and odds ratios were pooled to calculate the effect size for the neutrophil-lymphocyte ratio in acute stroke patients. We defined poor function outcomes according to the modified Rankin Scale ≥ 3 or Glasgow Outcome Scale< 3.Thirteen studies with 4443 patients were included in our analysis, including 7 ischemic and 6 hemorrhagic stroke studies. The pooled odds ratios for poor functional outcome at 3 months with a higher neutrophil-lymphocyte ratio in acute ischemic and hemorrhagic patients were 1.689 (95% CI = 1.184-2.409, p < 0.001) and 1.125 (95% CI = 1.022-1.239, p < 0.001), respectively, and the overall pooled odds ratio for poor functional outcome following stroke was 1.257 (95% CI = 1.146-1.379, p < 0.001). At the same time, the overall combined odds ratio for death at 3 months was 1.632 (95% CI = 1.155-2.306, p < 0.001).The neutrophil-lymphocyte ratio, an easily calculated marker, plays a predictive role in the short-term outcomes of adult patients (mean age ≥ 50 years) following acute ischemic and hemorrhagic stroke., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Long noncoding RNAs (lncRNAs) are a large group of noncoding RNAs 200 nucleotides long. lncRNAs that function as regulatory factors have been identified for several complex cellular processes, such as cell death, growth, differentiation, apoptosis, epigenetic regulation, and so on. Many lncRNAs have altered expression and are likely to play a functional role in oncogenesis. The pituitary adenoma is the second most common intracranial tumor. Despite this situation, the molecular mechanism of pituitary adenoma formation has not yet been fully identified. This review summarizes recent progress in the study of lncRNAs on the pathogenesis of pituitary tumors. We cover the latest results associated with this role and highlight the therapeutic possibilities for pituitary adenomas., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Spontaneous intracerebral hemorrhage (ICH) is a common and severe neurological disorder that has been associated with high rates of mortality and morbidity. It is urgent to find new biomarkers for the early diagnosis and prevention of ICH. In recent years, micro-RNAs (miRNAs) have been proved to play an important role in vascular damage and inflammation in cerebrovascular diseases, including ICH. In the peripheral blood, circulating miRNAs will be present at a remarkably steady level. In the present study, we explored the circulating plasma microRNA (miR)-181b, miR-223, miR-155, and miR-145 as new potential biomarkers for the diagnosis of ICH., Methods: The plasma samples from 106 patients with ICH and 50 patients without ICH (control group) were collected and subjected to quantitative real-time polymerase chain reaction analyses for the expression levels of circulating miR-181b, miR-223, miR-155, and miR-145., Results: The expression levels of plasma circulating miR-145 (P < 0.001), miR-223, and miR-155 were increased in patients with ICH compared with those in the control group (P < 0.05). However, the expression of plasma circulating miR-181b was decreased in patients with ICH compared with that in the control group (P < 0.001). Receiver operating characteristic curve analyses were performed to determine the diagnostic sensitivity and specificity of miR-145 and miR-181b to detect ICH. The area under the curve for miR-145 was 0.766 (95% confidence interval, 0.689-0.838) and for miR-181b was 0.78 (95% confidence interval, 0.70-0.86), suggesting that circulating miR-145 and miR-181b can be used to differentiate patients with ICH from those without ICH., Conclusion: Our results have shown that measurement of circulating miR-181b, miR-223, miR-155, and miR-145 in plasma samples could serve as a potential noninvasive tool for ICH detection., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: It has been reported that microRNA-195 (miR-195) protects against chronic brain injury induced by chronic brain hypoperfusion. However, neither the expression profile of miR-195 nor its potential role during acute ischemic stroke has been investigated. In this study, the authors' aim was to verify the mechanism of miR-195 in acute ischemic stroke., Methods: The plasma levels of miR-195 expression were assessed using real-time PCR in 96 patients with acute ischemic stroke, and the correlation with the National Institutes of Health Stroke Scale score was evaluated. In addition, cerebral infarct volume, neurological score, and levels of miR-195 and CX3CL1/CX3CR1 mRNA and protein expression were assessed in mice subjected to middle cerebral artery occlusion (MCAO) with or without intra-cerebroventricular infusion of lentiviral vector. The inflammatory cytokines tumor necrosis factor-α (TNFα), interleukin (IL)-1β, and IL-6 of mouse brains after MCAO and BV2 cells treated with oxygen-glucose deprivation were measured using enzyme-linked immunosorbent assay, and apoptotic proteins were examined by Western blotting. Direct targeting of CX3CL1/CX3CR1 by miR-195 was determined by immunoblotting and dual luciferase assay., Results: In ischemic stroke patients, miR-195 was significantly downregulated and expression levels of miR-195 in these patients negatively correlated with the National Institutes of Health Stroke Scale score. In mice after MCAO, miR-195 overexpression decreased infarct volume, alleviated neurological deficits, and most importantly, suppressed an inflammatory response. Meanwhile, miR-195 suppressed the expression of the inflammatory cytokines TNFα, IL-1β, and IL-6 in vitro and in vivo. The authors further discovered that both CX3CL1 and CX3CR1 are direct targets of miR-195, but miR-195 exerts neuroprotective roles mainly through inhibiting CX3CR1-mediated neuroinflammation and subsequent neuronal cell apoptosis., Conclusions: Taken together, these findings suggest that miR-195 promotes neuronal cell survival against chronic cerebral ischemic damage by inhibiting CX3CR1-mediated neuroinflammation. This indicates that miR-195 may represent a novel target that regulates neuroinflammation and brain injury, thus offering a new treatment strategy for cerebral ischemic disorders.

Glioblastoma is the most common and aggressive primary brain tumor in adults. New drug design and development is still a major challenge for glioma treatment. Increasing evidence has shown that nitazoxanide, an antiprotozoal drug, has a novel antitumor role in various tumors and exhibits multiple molecular functions, especially autophagic regulation. However, whether nitazoxanide-associated autophagy has an antineoplastic effect in glioma remains unclear. Here, we aimed to explore the underlying molecular mechanism of nitazoxanide in glioblastoma. Our results showed that nitazoxanide suppressed cell growth and induced cell cycle arrest in glioblastoma by upregulating ING1 expression with a favorable toxicity profile. Nitazoxanide inhibited autophagy through blockage of late-stage lysosome acidification, resulting in decreased cleavage of ING1. A combination with chloroquine or Torin1 enhanced or impaired the chemotherapeutic effect of nitazoxanide in glioblastoma cells. Taken together, these findings indicate that nitazoxanide as an autophagy inhibitor induces cell cycle arrest in glioblastoma via upregulated ING1 due to increased transcription and decreased post-translational degradation by late-stage autophagic inhibition.

Mitochondrial ferritin (FtMt) is believed to play an antioxidant role via iron regulation, and FtMt gene mutation has been reported in age-related macular degeneration (AMD). However, little is known about FtMt's functions in the retina and any links to AMD. In this study, we observed age-related increase in FtMt and hypoxia-inducible factor-1α (HIF-1α) in murine retinal pigment epithelium (RPE). FtMt overexpression in ARPE-19 cells stabilized HIF-1α, and increased the secretion of vascular endothelial growth factor. Conversely, HIF-1α stabilization reduced the protein level of the mature, functional form of FtMt. FtMt-overexpressing ARPE-19 cells exhibited less oxidative phosphorylation but unchanged production of adenosine triphosphate, enhanced mitochondrial fission, and triggered mitophagy in a HIF-1α-dependent manner. These findings suggest that increased FtMt in RPE may be protective via triggering mitophagy but cause wet AMD by inducing neovascularization due to increased vascular endothelial growth factor secretion. However, reduced level of functional FtMt in RPE under hypoxia may allow dry AMD through susceptibility to age-related stress., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

microRNAs (miRNAs) are commonly altered in glioblastoma. Publicly available algorithms suggest the Wnt pathway is a potential target of miR-577 and the Wnt pathway is commonly altered in glioblastoma. Glioblastoma has not been previously evaluated for miR-577 expression. Glioblastoma tumors and cell lines were evaluated for their expression of miR-577. Cell lines were transfected with miR-577, miR-577-mutant, or control mimics to evaluate the effect of miR-577 expression on cell proliferation in vitro and in an animal model. Wnt pathway markers were also evaluated for their association with miR-577 expression. miR-577 expression was decreased in 33 of 40 (82.5%) glioblastoma tumors and 5 of 6 glioblastoma cell lines. miR-577 expression correlated negatively with cell growth and cell viability. miR-577 down-regulation was associated with increased expression of the Wnt signaling pathway genes lipoprotein receptor-related protein (LRP) 6 (LRP6) and β-catenin. Western blot analysis confirmed decreased expression of the Wnt signaling pathway genes Axin2, c-myc, and cyclin D1 in miR-577 transfected cells. miR-577 expression is down-regulated in glioblastoma. miR-577 directly targets Wnt signaling pathway components LRP6 and β-catenin. miR-577 suppresses glioblastoma multiforme (GBM) growth by regulating the Wnt signaling pathway., (© 2015 Wiley Periodicals, Inc.)

Glioma is the most common primary brain tumor in the central nervous system (CNS) with high morbidity and mortality in adults. Although standardized comprehensive therapy has been adapted, the prognosis of glioma patients is still frustrating and thus novel therapeutic strategies are urgently in need. Quercetin (Quer), an important flavonoid compound found in many herbs, is shown to be effective in some tumor models including glioma. Recently, it is reported that adequate regulation of autophagy can strengthen cytotoxic effect of anticancer drugs. However, it is not yet fully clear how we should modulate autophagy to achieve a satisfactory therapeutic effect. 3-Methyladenine (3-MA) and Beclin1 short hairpin RNA (shRNA) were used to inhibit the early stage of autophage while chloroquine (CQ) to inhibit the late stage. MTT assay was implemented to determine cell viability. Transmission electron microscopy, western blot, and immunohistochemistry were adopted to evaluate autophagy. Western blot, flow cytometry, and immunohistochemistry were used to detect apoptosis. C6 glioma xenograft models were established to assess the therapeutic effect (the body weight change, the median survival time, and tumor volume) in vivo. Quercetin can inhibit cell viability and induce autophagy of U87 and U251 glioma cells in a dose-dependent manner. Inhibition of early-stage autophagy by 3-MA or shRNA against Beclin1 attenuated the quercetin-induced cytotoxicity. In contrast, suppression of autophagy at a late stage by CQ enhanced the anti-glioma efficiency of quercetin. Therapeutic effect of quercetin for malignant glioma can be strengthened by inhibition of autophagy at a late stage, not initial stage, which may provide a novel opportunity for glioma therapy.

Glioma cells rely on glycolysis to obtain energy and sustain their survival under microenvironmental stress in vivo. The mechanisms of regulation of glycolysis in glioma cells are unclear. Signaling pathway mediated by the transcription factor X box-binding protein 1 (XBP1) is one of the most important pathways of unfolded protein response which is comprehensively activated in cancer cells upon the microenvironmental stress. Here we showed that XBP1 was significantly activated in glioma tissues in vivo. XBP1 silencing resulted in decreasing of glioma cell viability and ATP/lactate production under hypoxia, which is possibly mediated by inhibition of Hexokinase II (HK2)'s expression. More importantly, XBP1 silenced glioma cells showed the decrease of tumor formation capacity. Our results revealed that XBP1s activation was involved in glioma glycolysis regulation and might be a potential molecular target for glioma treatment.

A recent genome-wide association study has identified an association between rs1920116 near TERC and high-grade glioma in populations of European ancestry. In order to evaluate the effect of the SNP rs1920116 near TERC in the Chinese population, we examined associations of this candidate SNP with glioma in a sample of 1970 Chinese Han individuals. SNP genotype data were available for 980 Chinese glioma patients and 990 healthy controls. Logistic regression analyses were performed to evaluate the association between rs1920116 and glioma risk adjusted for age, gender and stratified by tumor grade where appropriate. The allele G at TERC rs1920116 are risk factors for gliomas, and its association with glioma risk was consistent across tumor subgroups in the Chinese Han population (OR = 1.18-1.21). In order to assess variation in SNP effect size at different patient ages, glioma cases and controls were divided into 3 age strata, in years: <50, 50-59, and 60+. The results of multiple logistic regression analyses indicate that the SNP has age-specific effects on the risk of developing glioma. Our report confirmed the effects of rs1920116 near TERC on glioma occurring in older peoples in the Chinese Han population for the first time. As TERC is a candidate for inter-individual variation in telomere length, our study supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life.

Subarachnoid hemorrhage (SAH) is an important cause of mortality in stroke patients. Long non-coding RNAs (LncRNAs) have important functions in brain disease, however their expression profiles in SAH remain to be elucidated. The present study aimed to investigate the expression signatures of LncRNAs and mRNAs in early brain injury (EBI) following SAH in a rat model. Male Wistar rats were randomly divided into an SAH group and a sham operation group. The expression signatures of the LncRNAs and mRNAs in the temporal lobe cortex were investigated using a rat LncRNAs array following experimental SAH. The results revealed that there were 144 downregulated and 64 upregulated LncRNAs and 181 downregulated and 221 upregulated mRNAs following SAH. Additionally, two upregulated (BC092207, MRuc008hvl) and three downregulated (XR&#95;006756, MRAK038897, MRAK017168) LncRNAs were confirmed using reverse transcription quantitative polymerase chain reaction. The differentially expressed mRNAs were further analyzed using the Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The pathway analysis results provided by the KEGG database indicated that eight pathways associated with inflammation were involved in EBI following SAH. In conclusion, these results demonstrated that the expression profiles of the LncRNAs and mRNAs were significantly different between the SAH-induced EBI group and the sham operation group. These differently expressed LncRNAs may be important in EBI following SAH.

Glioblastoma multiforme (GBM) is the most malignant brain tumor in humans. Previous studies have demonstrated that microRNA plays important roles in the development and proliferation of GBM cells. Here we defined the mechanism by which miR-212-3p regulated the proliferation of GBM. In this study, we showed that miR-212-3p expression was significantly down-regulated and negatively correlated with serum and glucocorticoid-inducible kinase 3 (SGK3) in GBM. Either over-expression of miR-212-3p or silence of SGK3 decreased viability of GBM cells. Moreover, miR-212-3p directly bound to 3'UTR of SGK3 and inhibited its mRNA and protein expression. And over-expression of SGK3 rescued the decreased proliferation of GBM cells induced by miR-212-3p. Importantly, miR-212-3p also suppressed tumor growth in vivo. Collectively, our results demonstrated that miR-212-3p inhibited proliferation of GBM cells by directly targeting SGK3, and could potentially serve as a new therapeutic target for GBM.

MicroRNAs (miRNAs) are small noncoding RNAs that have been critically implicated in several human cancers. miRNAs are thought to participate in various biological processes, including proliferation, cell cycle, apoptosis, and even the regulation of the stemness properties of cancer stem cells. In this study, we explore the potential role of miR-300 in glioma stem-like cells (GSLCs). We isolated GSLCs from glioma biopsy specimens and identified the stemness properties of the cells through neurosphere formation assays, multilineage differentiation ability analysis, and immunofluorescence analysis of glioma stem cell markers. We found that miR-300 is commonly upregulated in glioma tissues, and the expression of miR-300 was higher in GSLCs. The results of functional experiments demonstrated that miR-300 can enhance the self-renewal of GSLCs and reduce differentiation toward both astrocyte and neural fates. In addition, LZTS2 is a direct target of miR-300. In conclusion, our results demonstrate the critical role of miR-300 in GSLCs and its functions in LZTS2 inhibition and describe a new approach for the molecular regulation of tumor stem cells.

Background: Gliomas account for almost 80% of primary malignant brain tumors. Epidermal growth factor (EGF) is an interesting research candidate in which to look for genetic polymorphisms because of its role in mitogenesis and proliferation. Extensive studies have found that a single nucleotide polymorphism (SNP) +61 G/A (rs4444903) in the EGF gene is associated with the susceptibility of glioma, however, the results have been controversial. Furthermore, the association between EGF +61 G/A polymorphism with the development and grade progress of glioma has not been established., Methods: We examined the association of EGF +61 G/A polymorphism and glioma by performing a meta-analysis. Nine studies testing the associations between EGF +61 G/A polymorphism and risk of glioma with 1758 cases and 2823 controls were retrieved. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. The pooled ORs were performed for the allele model, codominant model, dominant model, and recessive model, respectively., Results: Overall, this meta-analysis showed significant associations between the EGF +61 G/A polymorphism and glioma susceptibility in all four genetic models. However, in the stratified analysis by the grade of glioma, we only found this association existed in patients with Grade IV glioblastoma, but not in patients with Grade I-III glioma. We further compared EGF +61 G/A polymorphism in patients with glioblastoma and Grade I-III glioma accordingly, the stronger association between the EGF +61 G/A polymorphism and the malignancy of glioma was found., Conclusions: The results of this meta-analysis suggested that the EGF +61 G/A polymorphism is associated with both the susceptibility of glioma and the malignance of glioma.

Deposition of extracellular matrix (ECM) in trabecular meshwork, such as fibronectin, collagen IV, elastin. leads to increased resistance of trabecular meshwork in primary open angle glaucoma (POAG). Connective tissue growth factor (CTGF) is known to regulate the ECM deposits. In this study, we detect the effect of adenovirus conducted CTGF (Adv-CTGF) transfection on either the expression of ECM components or aqueous humor outflow facility. Adv-CTGF was used to transfect rat trabecular meshwork cells in vivo and in vitro. Aqueous humor outflow facility was test by microbeads perfusion. Protein expression of CTGF, fibronectin, and collagen IV was determined using Western blot. In the Adv-CTGF group, the outflow facility displayed a significant decrease from baseline. It appears as though the transfection with Adv-CTGF significantly affects the aqueous humor outflow pattern. A negative correlation between IOP and PEFL indicated that a decrease in the area of bead deposition corresponded to an overall decrease of outflow, leading to an elevated IOP. Adv-CTGF can enhance the expression of CTGF, fibronectin and collagen IV. CTGF is the novel target for treatment of POAG. It is necessary to further study to test inhibition of CTGF expression for treatment of POAG.

Among glioma treatment strategies, 5-aminolevulinic acid (5-ALA)-based fluorescence-guided resection (FGR) and photodynamic therapy (PDT) have been used as effective novel approaches against malignant glioma. However, insufficient intracellular protoporphyrin IX (PpIX) accumulation limits the application of FGR and PDT in the marginal areas of gliomas. To overcome these issues, we assessed the intracellular levels of PpIX in human glioma cell lines and rat cortical astrocytes pretreated with 0.1μM arsenic trioxide (ATO). Apoptosis and cell viability after PDT were evaluated using Annexin V-FITC apoptosis detection kit and MTT assay, respectively. In order to find out the possible mechanism, we investigated the expression of the key enzymes in the heme biosynthesis pathway, which regulates porphyrin synthesis in glioma cells. Our findings showed that the 5-ALA-induced PpIX accumulation in glioma cell lines pretreated with 0.1μM ATO was increased relative to the control groups. No changes in fluorescence intensity were detected in the rat cortical astrocytes pretreated using the same ATO concentration. Apoptosis following PDT in glioma cells pretreated with 0.1μM ATO were significantly higher than in control groups, especially late apoptotic cells, while the cell viability was decreased. The expression of CPOX was upregulated in glioma cells after pretreatment with 0.1μM ATO. We concluded that ATO was a potential optional approach in enhancing intracellular PpIX accumulation and improving the benefits of 5-ALA-induced FGR and PDT in glioma., (Copyright © 2013. Published by Elsevier B.V.)

Notch signaling has been demonstrated to have a central role in cancer stem-like cells (CSLCs) in glioblastoma multiforme (GBM). We have recently demonstrated the inhibitory effect of arsenic trioxide (ATO) on CSLCs in glioblastoma cell lines. In this study we used neurosphere recovery assay that measured neurosphere formation at three time points to assess the capacity of the culture to repopulate after ATO treatment. Our results provided strong evidence that ATO depleted CSLCs in GBM, and inhibited neurosphere recovery and secondary neurosphere formation. ATO inhibited the phosphorylation and activation of AKT and STAT3 through Notch signaling blockade. These data show that the ATO is a promising new approach to decrease glioblastoma proliferation and recurrence by downregulation of Notch pathway., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Glioblastomas rely mainly on aerobic glycolysis to sustain proliferation and growth; however, little is known about the regulatory mechanisms of metabolism in glioblastoma stem cells. We show that miR-143 is significantly down-regulated in glioma tissues and glioblastoma stem-like cells (GSLCs), while miR-143 over-expression inhibits glycolysis by directly targeting hexokinase 2, and promotes differentiation of GSLCs. Moreover, miR-143 inhibits proliferation of GSLCs under hypoxic conditions and decreases tumor formation capacity of GSLCs in vivo. We also show that a combination of miR-143 and 2-DG, a widely used glycolysis inhibitor, has synergistic effects against GSLCs. miR-143 is a potential therapeutic target for glioblastoma treatment., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Glioblastoma multiforme (GBM) is lethal brain tumor thought to arise from GBM stem cells (GBM-SCs). MicroRNAs carry out post-transcriptional regulation of various cellular processes that modulate the stemness properties of GBM-SCs. Here, we investigated the critical role of miR-153 in GBM-SCs. First, GBM-SCs were isolated from six GBM specimens. These GBM-SCs formed GBM spheres, expressed markers associated with neural stem cells, and possessed the capacity for self-renewal and multilineage differentiation. Then qRT-PCR analysis showed that miR-153 expression was down-regulated in GBM tissues relative to normal brain tissues, and in CD133 positive cells relative to CD133 negative cells. This project demonstrates for the first time that transient transfection of miR-153 into GBM-SCs can inhibit their stemness properties, such as impairing self-renewal ability and inducing differentiation. Meanwhile, miR-153 can also repress GBM-SCs growth and induce apoptosis. Altogether, these results indicate that reactivation of miR-153 expression suggests novel therapeutic strategies for GBM-SCs.

Harmine hydrochloride (Har-hc), a derivative from Harmine which is a natural extractive from plants, has been considered for treatment of kinds of cancers and cerebral diseases. In this study, we found that Har-hc clearly decreased cell viability, induced apoptosis and inhibited Akt phosphorylation in glioblastoma cell lines. Moreover, Har-hc had the ability to inhibit self-renewal and promote differentiation of glioblastoma stem like cells (GSLCs) accompanied by inhibition of Akt phosphorylation. Especially, we demonstrated that Har-hc inhibited neurosphere formation of human primary GSLCs. In vivo test also confirmed Har-hc decreased the tumorigenicity of GSLCs. Thus we conclude that Har-hc has potent anti-cancer effects in glioblastoma cells, which is at least partially via inhibition of Akt phosphorylation. Administration of Har-hc may act as a new approach to glioblastoma treatment.

Background: Previous study indicated that PS-341 induces cell death via JNK pathway in vitro in glioma. However, suppressing proteasome complex by PS-341 may induce expression of heat shock proteins (HSPs), which confer potential protection against cellular stress. In this study, we explored whether induction of HSPs could impair PS-341-induced cell death and whether inhibition of HSPs could enhance cell damage induced by PS-341 in glioma cells., Methods: HSP expression in glioma cells was modulated by HSP inhibitor, sublethal heat, or knockdown of heat shock factor1 (HSF1), then PS-341-induced cell damage was examined by different methods. Similar experiments were also performed in HSF1+/+ and HSF1-/- cells. HSP70 expression and HSF1 nuclear localization were compared between glioma and normal brain tissues., Results: HSP level was upregulated mediated by HSF1 when glioma cells were treated with PS-341. PS-341-mediated cell damage could be significantly augmented by HSP inhibition. Furthermore, HSP70 expression and HSF1 nuclear localization were much more abundant in gliomas than in normal brain tissues., Conclusions: Our results demonstrated that HSP70 impaired cell death induced by PS-341 in glioma cells. Administration of PS-341 in combination with either HSP70 inhibitor or HSF1 knockdown may act as a new approach to treatment of glioma.

Although heat stress induces a variety of illnesses, there have been few studies designed to uncover the molecular mechanisms underlining the illnesses. We here demonstrate that heat activates ER stress, which inhibits heat shock responses (HSR) via translational block. In heat-stressed rats, ER stress responses, as represented by eIF2α phosphorylation and XBP1 splicing, occurred mainly in the cortex, where the HSR was substantially inhibited. Heat exposure also activated ER stress signals in primary cortical neurons. Since HSF1 knockdown enhanced heat-induced ER stress and subsequent cell death, HSR inhibition in turn augments ER stress, implying a vicious spiral of both stresses. Taken together, heat-induced ER stress impairs the HSR and enhances cell damage, thereby manifesting its unique effect on heat stress.

This study presents our findings on the extent of neuronal damage in the hippocampal CA1-4 subfields following global (forebrain) cerebral ischemia in rats when using different blood pressure levels (37 vs 45 mmHg) and bilateral carotid occlusion durations (8 vs 10 min) under isoflurane anesthesia. We observed that global ischemia induced at a blood pressure of 37 mmHg resulted in high-grade CA1 neuron injury (>90%) at either duration of carotid occlusion. In contrast, global ischemia induced at a blood pressure of 45 mmHg resulted in either high-grade CA1 neuronal loss or a neuronal loss of ≈50% or less. We also noted that a post-reperfusion EEG recovery time (return of burst suppression spikes) of >12 min was associated with an 85% rate of high-grade CA1 neuronal injury. Neuronal loss in the other hippocampal subfields did not differ significantly between any of the 4 different model parameters tested. In these subfields ≈55% neuronal loss occurred in the CA2 subfield, and ≈30% in the CA3 and CA4 subfields. These findings highlight the need to assess different model parameters in order to achieve consistent high-grade CA1 neuronal damage, which, among other experimental outcomes, will improve the ability to uncover therapeutic effects using the least possible animals when assessing a neuroprotective treatment., (Copyright © 2011 Elsevier Inc. All rights reserved.)

MicroRNAs are single-stranded small non-coding RNA molecules which regulate mammalian cell growth, differentiation, and apoptosis by altering the expression of other genes and play a role in tumor genesis and progression. MiR-106a is upregulated in several types of malignancies and provides a pro-tumorigenic effect. However, its role in glioma is largely unknown. Our findings demonstrate that the low expression of miR-106a in human glioma specimens is significantly correlated with high levels of E2F1 protein and high-grade glioma. Here, we present the first evidence that miR-106a provides a tumor-suppressive effect via suppressing proliferation of and inducing apoptosis in human glioma cells. We further show that E2F1 is a direct functional target of miR-106a, suggesting that the effect of miR-106a on the glioma suppressive effect may result from inhibition of E2F1 via post-transcriptional regulation. In addition, our results reveal that miR-106a can increase p53 expression via E2F1 inhibition, whereas the effect of miR-106a on the proliferation of glioma cells is independent of p53 status. Further investigations will focus on the therapeutic use of miR-106a-mediated antitumor effects in glioma.

We have previously reported that arsenic trioxide (ATO) could inhibit glioma growth both in vitro and in vivo, and demonstrated its potent therapeutic effects on gliomas. In this study we showed that ATO induced cell damage and heme oxygenase-1 (HO-1) expression in glioma cells via ROS generation. HO-1 inducer clearly protected from ATO-induced cell death and ROS generation, and HO-1 inhibitor led to a significant increase in cell death and ROS generation induced by ATO. In addition, knockdown of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) strongly inhibited HO-1 expression induced by ATO, and significantly enhanced ATO-induced oxidative damage. Our results demonstrated, for the first time, that HO-1 inhibition or Nrf2 knockdown significantly potentiated ATO's effects on glioma cells. Considering that HO-1 is highly expressed in glioma tissues, administration of ATO in combination with either HO-1 inhibitor or Nrf2 knockdown may act as a new approach to the treatment of glioma.

A better understanding of the underlying mechanisms of angiogenesis and vascular permeability is necessary for the development of therapeutic strategies for ischemic injury. The purpose of this study was to examine the spatial and temporal expression of Src and Src-suppressed C kinase substrate (SSeCKS) in brain after middle cerebral artery occlusion (MCAO) and elucidate the relationships among Src, SSeCKS, and the key angiogenic factors present after stroke. Rats were subjected to either MCAO or sham operation. Reverse transcriptase-polymerase chain reaction and Western blotting results revealed that Src gradually increased starting as early as 2 h after MCAO and remained high for 1 day. In contrast, SSeCKS decreased after MCAO. Src expression correlated positively with that of vascular endothelial growth factor and angiopoietin-2, and negatively with that of SSeCKS, angiopoietin-1, and zonula occludens-1. However, SSeCKS had the reverse correlations. Changes in the expression of these factors correlated with the progress of angiogenesis and cerebral edema. Dynamic temporal changes in Src and SSeCKS expression may modulate angiogenesis and cerebral edema formation after focal cerebral ischemia., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

MicroRNAs (miRNAs) are small noncoding RNAs that take part in diverse biological processes by suppressing target gene expression. Elevated expression of miR-21 has been reported in many types of human cancers. Radiotherapy is a standard adjuvant treatment for patients with glioblastoma. However, the resistance of glioblastoma cells to radiation limits the success of this treatment. In this study, we found that miR-21 expression was upregulated in response to ionizing radiation (IR) in U251 cells, which suggested that miR-21 could be involved in the response of U251 cells to radiation. We showed that a miR-21 inhibitor enhanced IR-induced glioblastoma cell growth arrest and increased the level of apoptosis, which was probably caused by abrogation of the G(2)-M arrest induced by IR. Further research demonstrated that the miR-21 inhibitor induced the upregulation of Cdc25A. Taken together, these findings suggest that miR-21 inhibitor can increase IR-induced growth arrest and apoptosis in U251 glioblastoma cells, at least in part by abrogating G(2)-M arrest, and that Cdc25A is a potential target of miR-21.

Background: This study was to delineate the therapeutic efficacy and potential cellular and molecular mechanisms of aminoguanidine (AG), a relatively selective inhibitor of iNOS activity, in cerebral vasospasm after subarachnoid hemorrhage (SAH) in rabbits., Methods: SAH was induced by a single injection of autologous arterial blood into the cisterna magna of adult male rabbits. An intravenous bolus injection of AG (150 mg/kg) was administrated 1h after SAH, and this dosage was repeated on the following day. Vasospasm was verified by computed tomography angiography (CTA) day 2 after SAH. Rabbit basilar arteries were harvested for transmission electron microscopy (TEM), immunohistochemical examination, RT-PCR, and western blot analysis., Results: CTA data revealed that cerebral vasospasm of SAH rabbits was significantly prevented via AG treatment. TEM results demonstrated the ultrastructural morphological changes of endothelial cells of SAH rabbits were ameliorated by AG treatment. In parallel, AG treatment increased eNOS mRNA and protein levels along with the reduced immunoreactivity of nitrotyrosine in rabbit basilar arteries., Conclusions: Our discovery suggested AG inhibition of iNOS activity could significantly reverse cerebral vasospasm after SAH via restoration of dysfunctional endothelial cells by the upregulation of eNOS, indicating a regulatory cross-talk between eNOS and iNOS in the pathogenesis of SAH., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Cancer stem-like cells (CSLCs) are potential targets for treatment of glioblastoma multiforme (GBM) due to their role in tumorigenesis and recurrence. In this study, we investigated the inhibitory effect of arsenic trioxide (As(2)O(3)) on CSLCs of GBM in human glioma cell lines (U87MG, U251MG and U373MG) in vivo and in vitro. Immunofluorescence staining and flow cytometry revealed that the percentage of Nestin-positive cells in the aforementioned cell lines was diminished by 12%, 14% and 7%, respectively, after treatment with 2 microM As(2)O(3). Furthermore, we used soft-agar in U87MG and tumor xenografts in nude mice to demonstrate the ability of As(2)O(3) to inhibit the formation of tumor in the three cell lines. These results indicate the negative regulation of CSLCs by As(2)O(3). In addition, a Western blot analysis revealed decreased levels of Notch1 and Hes1 proteins due to As(2)O(3) treatment. We conclude that As(2)O(3) has a remarkable inhibitory effect on CSLCs in glioma cell lines in vivo and in vitro; in addition, we determined that the mechanism of CSLC inhibition involves the deregulation of Notch activation., (Copyright (c) 2009 Elsevier Ireland Ltd.All rights reserved.)

Cordycepin has the effect of anti-tumor, immunomodulation, anti-inflammation and so on. In order to make use of Cordyceps militaris better, we implanted different doses of low-energy ion beam into C. militaris, chose best cordycepin extracting technology, and determined cordycepin content in strains before and after ion beam implantation by UV spectrophotometry. Results showed that the best dose of low-energy ion beam was 2.60 x 10(15) ions/cm2, the best conditions of microwave assisted ultrasonic extraction technology were as follows: 70% ethanol as the solvent, microwave power as 200 W, extraction time as 110 s, Material - liquid ratio as 1: 240. We chose 15 strains with high-yielding cordycepin, of which cordycepin content was up to (11.924 +/- 0.063) mg/g, which was a nearly 30% increase compared with the original strain.

Edema formation has been linked to thrombin toxicity induced by blood clot at the acute stage of intracerebral hemorrhage. Thrombin induces cell toxicity in neuron, microglia and astrocyte. Aquaporin (AQP) 4 and 9 are proteins expressed on astrocyte in rat brain and involved in the brain water accumulation in brain edema. Recombinant hirudin (r-Hirudin) is a direct inhibitor of thrombin that can block the toxicitic effect of thrombin. In this study, we demonstrated that autologous whole blood infusion in caudate nucleus up-regulates the expression of AQP4 and AQP9 mRNAs and proteins. AQP4 and AQP9 mRNAs expression peaked at about 6 h after blood infusion. The AQP4 protein peaked at about 48 h while AQP9 at about 24 h after blood infusion. Thrombin induced up-regulation of AQP4 and AQP9 were inhibited by r-Hirudin administration and significantly decreased the expression of both AQPs. We further investigated the relationship between edema formation and expression of AQP4 and AQP9. The data presented here may be helpful in optimizing r-Hirudin as an anti-thrombin drug in the treatment of edema at the acute stage of ICH.

We have previously reported that As(2)O(3) affected cell cycle progression and cyclins D1 and B1 expression in two glioma cell lines differing in p53 status (U87MG-wt; T98G-mutated). In the present study, we further demonstrated that As(2)O(3) affected proliferation, viability and apoptosis of the two cell lines in a dose- and time-dependent manner, and T98G cells were more sensitive than U87MG cells to As(2)O(3) -induced apoptosis and inhibition of proliferation and viability. We further investigated the expression profiles of genes related with apoptosis and cell cycle in the two cell lines with a human cDNA-microarray (SuperArray) spotted with 267 genes of apoptosis and cell cycle. Thirty five genes were upregulated and 15 genes downregulated at least 2-fold by As(2)O(3) in U87-MG cells; whereas, 38 genes were upregulated and 21 genes downregulated at least 2-fold in T98G cells by As(2)O(3). After As(2)O(3) treatment, p53 expression was upregulated 56.5-fold in T98G cells, but only 6.0-fold in U87MG cells. The results indicate that As(2)O(3) suppresses the growth of U87MG cells mainly by regulating expression of genes of cell cycle arrest, stress and toxicity; whereas As(2)O(3) affects T98G cells mainly by regulating expression of genes belonging to Bcl-2, tumor necrotic factor receptor and ligand families. The data may be helpful for optimizing As(2)O(3) as an anti-cancer drug in the treatment of gliomas.